eravacycline and Escherichia-coli-Infections

Extended-spectrum cephalosporin-resistant Escherichia coli (ESCREC) are a growing threat. Leading ESCREC lineages include sequence type ST131, especially its (bla

Topics: Adult; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Drug Combinations; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Tetracyclines; Young Adult

Eravacycline (formerly TP-434) was evaluated in vitro against pre-established biofilms formed by a uropathogenic Escherichia coli strain. Biofilms were eradicated by 0.5 μg/ml eravacycline, which was within 2-fold of the MIC for planktonic cells. In contrast, colistin and meropenem disrupted biofilms at 32 and 2 μg/ml, respectively, concentrations well above their respective MICs of 0.5 and 0.03 μg/ml. Gentamicin and levofloxacin eradicated biofilms at concentrations within 2-fold of their MICs.

Topics: Anti-Bacterial Agents; Biofilms; Colistin; Colony Count, Microbial; Escherichia coli Infections; Gentamicins; Humans; Levofloxacin; Meropenem; Microbial Sensitivity Tests; Tetracyclines; Thienamycins; Urinary Tract Infections; Uropathogenic Escherichia coli

Eravacycline is a novel broad-spectrum fluorocycline with potent Gram-negative activity, including for multidrug-resistant strains. Among 472 Escherichia coli clinical isolates from 24 Veterans Affairs medical centers (in 2011), divided equally as susceptible versus resistant to fluoroquinolones, broth microdilution eravacycline MICs were distributed unimodally, ranging from 0.03 to 1.0 μg/ml (MIC50 of 0.125 μg/ml, MIC90 of 0.25 μg/ml). Eravacycline MICs were ∼ 2-fold higher among fluoroquinolone-resistant, gentamicin-resistant, multidrug-resistant, and sequence type 131 (ST131) isolates (P < 0.01 for each comparison).

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Humans; Microbial Sensitivity Tests; Tetracyclines; United States; Veterans

This and the accompanying report (DOI: 10.1021/jm201467r ) describe the design, synthesis, and evaluation of a new generation of tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines ("fluorocyclines"), accessible through a recently developed total synthesis approach. These fluorocyclines possess potent antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. One of the fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline (17j, also known as TP-434, 50th Interscience Conference on Antimicrobial Agents and Chemotherapy Conference , Boston, MA , September 12-15, 2010 , poster F1 - 2157 ), is currently undergoing phase 2 clinical trials in patients with complicated intra-abdominal infections (cIAI).

Topics: Animals; Anti-Bacterial Agents; Cyclophosphamide; Drug Resistance, Multiple, Bacterial; Escherichia coli Infections; Gram-Negative Bacteria; Gram-Positive Bacteria; Male; Methicillin Resistance; Mice; Microbial Sensitivity Tests; Neutropenia; Pyrrolidines; Rats; Rats, Sprague-Dawley; Ribosomes; Sepsis; Stereoisomerism; Structure-Activity Relationship; Tetracycline Resistance; Tetracyclines